Abstract The overall goal of this project is to continue development of an attention bias modification (ABM) intervention that targets and reduces negative attention bias among adults with elevated symptoms of depression. Our prior work indicates that attention bias for negative information is associated with the maintenance of depression and that neural circuitry within frontal-parietal brain networks supports biased attention for negative information, thus allowing us to develop specific and targeted interventions that directly alter the neurobiology of negative attention bias. The proposed R33 study builds upon our prior NIMH funded work (R21MH092430), which examined whether ABM reduces negative attention bias and improves symptoms of depression. Findings indicate that compared to placebo ABM, active ABM reduced negative attention bias and increased resting state connectivity within a neural circuit (i.e., middle frontal gyrus and dorsal anterior cingulate cortex) that supports control over emotional information. Further, change in negative attention bias from pre- to post-ABM was significantly correlated with depression symptom change but only in the active training condition. Importantly, a 40% decrease in symptoms was observed in the active training condition; however, similar symptom reduction was also observed in the ?placebo ABM? condition. Exploratory analyses indicated that placebo training may have promoted depression improvement by enhancing sustained attention. Although these preliminary findings are encouraging and demonstrate that ABM successfully alters the treatment target (i.e., negative attention bias), our prior work is among the first to document efficacy of ABM among adults with clinically significant depression. We believe it is prudent and necessary to obtain additional efficacy evidence for ABM before moving forward with large-scale clinical trials of ABM for depression. Aim 1 is to conduct a randomized clinical trial among adults with elevated symptoms of depression and a negative attention bias that compares the efficacy of active ABM to placebo ABM and an assessment-only control condition that does not involve any ABM procedures. Aim 2 is to examine whether ABM alters negative attention bias and functional connectivity within frontal-parietal neural circuitry that support negative attention bias. Aim 3 is to identify mechanisms responsible for the putative efficacy of active and placebo ABM. Study Impact: The current project proposes to target and reduce negative attention bias with a novel intervention grounded in basic psychopathology research. We believe this experimental medicine approach will lead to the development of a highly specific and targeted intervention, using cutting- edge cognitive neuroscience to inform treatment development, and improve the quality of life of people whose psychopathology is maintained by negative attention bias.